Benzyl methyl sulfones and process for preparing same

ABSTRACT

Benzyl methyl sulfones having anti-inflammatory, anti-pyretic and analgesic activity. Also included is a method of substituting a benzyl methyl sulfone.

nited States Patent Shen et al.

BENZYL METHYL SULFONES AND PROCESS FOR PREPARING SAME Inventors:Tsung-Ying Shen, 728 Tamagues Way; Clifford H. Shimk, 2057 W. Broad St.,both of Westfield, NJ.

Filed: Aug. 1, 1966 I Appl. No.: 569,039

Related US. Application Data Continuation-impart of Ser. No'. 458,435,May 24, 1965, abandoned.

[ 1 Sept. 5, 1972 [58] Field of Search ..260/607 A [5 6] ReferencesCited OTHER PUBLICATIONS Lewis et al., J.A.C.S. Vol. 73 (1951) pp.2,109-

Orda et al., Chem. Abstracts (1965) Vol. 63, pp. 1,684- 1,685

Mamalis 1,1, ghem s o c." (1960) pp. 4,7474,753 gggner et 91., Syn. Org.Cheffi." 1953) pp. 9 2 and Primary ExaminerJoseph Rebold AssistantExaminer-D. R. Phillips Attorney-I. Louis Wolk and Harry E. Westlake,Jr.

[57] ABSTRACT Benzyl methyl sulfones having anti-inflammatory,antipyretic and analgesic activity. Also included is a method ofsubstituting a benzyl methyl sulfone.

7 Claims, No Drawings PEERQCESS FUR a c s This application is acontinuation-in-part of our application Ser. No. 458,435, filed May 24,1965, now abandoned.

This invention relates to a method of treating inflammation utilizingnovel anti-inflammatory compositions containing aralkyl hydrocarbylsulfones. In addition, these novel compositions exhibit potent analgesicand antipyretic activity and, therefore, this invention also relates toanalgesic and antipyretic methods and compositions. More particularly,this invention is concemed with the use of benzyl methyl sulfones as theactive therapeutic ingredient in the herein described methods andcompositions.

This invention also relates to certain novel substituted benzyl methylsulfones of structural formula:

and processes for their preparation, wherein, R and R" are hydrogen,lower alkyl, lower alkenyl, phenyl, or loweralkoxycarbonyl with theproviso that if R and R" are the same they are hydrogen, lower alkyl, orphenyl and if they are different, one of them is hydrogen.

Z is hydrogen or fluorine. X and Y are hydrogen, hydroxyloweralkyl,aminoloweralkyl, diloweralkylaminoloweralkyl,

haloloweralkyl such as trifluoromethyl, lower alkoxy, phenyl, benzyloxy,fluoro, amino, diloweralkylamino, carboxy, loweralkoxycarbonyl,carbamoyl, N,N- diloweralkylcarbamoyl, or lower acyl, with the provisothat if Z is fluorine X and Y are hydrogen or fluorine, and if Z ishydrogen and X and Y are both other than hydrogen they are bothfluorine.

Benzyl methyl sulfone and the related aralkyl sulfones of this inventionrepresent a new milestone in the continuing search for potent, lowtoxicity, anti-inflammatory agents. These sulfones provide a uniquestructure-activity relationship which not only has resulted in highanti-inflammatory, antipyretic, and analgesic potency, but also appearto exhibit a biological profile quite different from the salicylates andphenylbutazone.

It is an object to this invention to provide a method of treatment ofinflammation and associated pain and fever in patients. It is also anobject of this invention to provide analgesic and antipyretic methodsfor the relief and treatment of pain and fever not symptomaticallyrelated to an inflammatory indication. Another object is to provide anentirely new class of anti-inflammatory, analgesic and antipyreticcompounds and compositions.

The above and other objects of this invention are accomplished byadministration to a patient in dosage unit form, a pharmaceuticallyacceptable composition containing a therapeutically effective amount ofan aralkyl sulfone, such as benzyl methyl sulfone. The sulfones of thenovel compositions of this invention can be represented by the followingformula:

wherein R is alkyl of from one to about 20 carbon atoms, preferablylower alkyl of from one to about eight carbons (such as methyl, propyl,pentyl and the like); cycloalkyl such as cyclohexyl and cyclopentyl,loweralkylcycloalkyl such as methylcyclohexyl, halocycloalkyl such aschlorocyclohexyl, lower alkenyl containing one or more double bonds andup to about eight carbon atoms, haloloweralkyl and haloloweralkenylbearing up to three halogens such as chlorine, bromine, and fluorine andup to about eight carbons and hydroxyloweralkyl, hydroxyloweralkenyl,loweralkoxyloweralkyl and loweralkoxyloweralkenyl, each containing up toabout eight carbon atoms.

R and R" are hydrogen, lower alkyl, lower alkenyl, phenyl, orloweralkoxycarbonyl with the proviso that if they are the same they arehydrogen, lower alkyl or phenyl and if they are different, one of themis hydrogen.

Z is hydrogen or fluorine. X and Y are hydrogen, halo, nitro, amino,diloweralkylamino, lower alkyl, aminoloweralkyl,diloweralkylaminoloweralkyl, hydroxyloweralkyl, phenoxyloweralkyl,haloloweralkyl, lower alkoity, phenyl, phenylloweralkoxy, or a radicalof the formula COA wherein A represents hydroxy, lower alkoxy, loweralkyl, amino, diloweralkylamino with the proviso that if Z is fluorine,X and Y are hydrogen or fluorine, and if X and Y are both other thanhydrogen they are lower alkyl, halo, or nitro. Unless otherwise noted,lower alkimplies of from one to about four carbons.

A preferred embodiment of this invention is a method of treating adisease which is symptomatically characterized by pain, fever and/orinflammation which comprises the administration to a patient in dosageunit form of between about 0.01 and 5 gm. of benzyl methyl sulfone perday. On a kilogram basis, it is preferred to utilize between about 0.5mg./kg. and mg./kg. per day of the aralkyl hydrocarbyl sulfones of thisinvention.

Another embodiment of this invention is the provision of pharmaceuticalcompositions in dosage unit form which comprise from about 5 to 500 mg.,and preferably from 25 to 250 mg., of an aralkyl hydrocarbyl sulfone ofthe above formula. Benzyl methyl sulfone, in oral dosage unit form,comprising about 25 to about 500 mg. is a preferred pharmaceuticalcomposition of this invention.

The aralkyl hydrocarbyl sulfone active ingredient of the compositions ofthis invention demonstrates significant anti-inflammatory analgesic andantipyretic properties. For example, anti-inflammatory activity of ahigh order of potency was shown for benzyl methyl sulfone againstcarrageenan edema, using the method set forth in Proc. Soc. Exp. Biol.Med. 3: 544 (1962). The minimum dose required for dependabledemonstration of anti-inflammatory activity was about 1 mg./kg. Thiscompound is also a potent analgesic, as has been shown byantinociceptive testing by the inflamed foot technique of Randall &Selitto, Arch. Int. Parmacodyn. 11: 409 (1957), as modified by Gilfoil,et al. (1963) and Winter, et a1. (1965). Benzyl methyl sulfone raisedthe pain threshold most significantly when compared to the controlstreated with the corresponding vehicle exclusive of said sulfone.Significant activity was observed at dosages as low as 3.33 mgJkg. andhigh potency was observed at 30 mg./kg. and 90 mg./kg. It is significantto note that the pain threshold was raised in both the infected andnoninfected foot. This is in contrast to currently used analgesics whichraise the pain threshold in the infected foot only.

An analgesic effect was also demonstrated in treatment of arthritisinduced hyperesthesia, utilizing a promising extremely sensitivetechnique which quantitatively records vocalization reduction. Accordingto this test, benzyl methyl sulfone is a potent analgesic at dosages aslow as 0.33 and l mg./kg. In addition, the sulfones of this invention,as exemplified by benzyl methyl sulfone, exhibit potent antipyreticactivity in yeast induced fever tests. Benzyl methyl sulfone wasdemonstrated to have antipyretic activity at dosages as low as 12.5mg./kg. Similarly anti-inflammatory, analgesic and antipyretic activitycan be demonstrated for other active sulfone ingredients of thisinvention, e.g., benzyl ethyl sulfone, benzyl propyl sulfone, benzylbutyl sulfone, benzyl t-butyl sulfone, benzyl cyclohexyl sulfone, benzylvinyl sulfone, benzyl 2-hydroxyethyl sulfone, o-methylbenzyl methylsulfone and ochlorobenzyl methyl sulfone.

Thus it can be seen that the novel sulfone compositions of thisinvention exercise anti-inflammatory, analgesic and antipyreticactivity.

Such pharmaceutical compositions may be in a form suitable for oral use,for example, as tablets, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to provide apharmaceutically elegant and palatable preparation. Tablets contain theactive sulfone ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for manufacture of tablets.These excipients may be, for example, inert diluents, for examplecalcium carbonate, sodium carbonate, lactose, calcium phosphate orsodium phosphate; granulating and disintegrating agents, for examplemaize starch, or alginic acid; binding agents, for example, starch,gelatine or acacia, and lubricating agents, for example, magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period.

Formulations for oral use may also be presented as hard gelatinecapsules wherein the active ingredient is mixed with an inert soliddiluent, for example calcium carbonate, calcium phosphate or kaolin, oras soft gelatine capsules wherein the active ingredient is mixed with anoil medium, for example arachis oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active aralkyl hydrocarbyl sulfones inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients are suspending agents, for example sodiumcarboxymethyl-cellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylvyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example, polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxy-cetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol, for example polyoxyethylene sorbitol mono-oleate, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example polyoxyethylene sorbitanmono-oleate. The said aqueous suspensions may also contain one or morepreservatives, for example, ethyl, or n-propyl, phydroxy benzoate, oneor more coloring agents, one or more flavoring agents and one or moresweetening agents, such as sucrose, saccharin, or sodium or calciumcyclamate.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents, such as those set forthabove and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample, olive oil or arachis oils, or a mineral oil for example, liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example, soya bean lecithin, andesters of partial esters derived from fatty acids and hexitolanhydrides, for example, sorbitan mono-oleate, and condensation productsof the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan mono-oleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative and flavoring and coloring agents. Thepharmaceutical compositions may be in the form of a sterile injectablepreparation, for example, as a sterile injectable aqueous suspension.This suspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1:3-butane diol.

The sulfone compositions of this invention may also be in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

The pharmaceutical compositions may be tableted or otherwise formulatedso that for every 100 parts by weight of the composition there arepresent between 5 and 95 parts by weight of the active ingredient andpreferably between 25 and 85 parts by weight of the active ingredient.The dosage unit form will generally contain between about 100 mg. andabout 500 mg. of the active ingredient of the formula stated above.

From the foregoing formulation discussion it is apparent that thecompositions of this invention can be administered orally, parenterally,topically and rectally. The term parenteral as used herein includessubcutaneous injection, intravenous, intramuscular, or intrasternalinjection or infusion techniques.

The dosage regimen in carrying out the methods of this invention is thatwhich insures maximum therapeutic response until improvement is obtainedand thereafter is the minimum effective level which gives relief. Thus,in general, the dosages are those that are therapeutically effective inthe treatment of inflammation, pain and fever. In general, the dailydose can be between about 0.5 mgjkg. and 70 mg./kg. bearing in mind ofcourse that in selecting the appropriate dosage in any specific case,consideration must be given to the patients weight, general health, ageand other factors which may influence response to the drug.

It is expected that the sulfone compositions of this invention willgenerally be administered in dosage units of between 5 and 500 mg. ofactive ingredient. Preferred compositions for ease, of administrationare in oral dosage unit form, e.g. tablets or capsules, containingbetween 25 and 500 mg. of a sulfone of this invention.

This invention is further demonstrated by the following examples inwhich all parts are by weight.

EXAMPLE 1 A mixture of 250 parts of benzyl methyl sulfone and 25 partsof lactose is granulated with suitable water, and to this is added 100parts of maize starch. The mass is passed through a 16 mesh screen. Thegranules are dried at a temperature below 60C. The dry granules arepassed through a 16 mesh screen, and mixed with 3.8 parts of magnesiumstearate. They are then compressed into tablets suitable for oraladministration.

The benzyl methyl sulfone used in the foregoing example may be replacedby 25, 100 or 500 parts of benzyl methyl sulfone, benzyl propyl sulfone,benzyl isopropyl sulfone, benzyl 2-methyl butyl sulfone, benzyl isobutylsulfone, benzyl t-butyl sulfone, benzyl l,l,3,3-tetramethylbutylsulfone, benzyl propenyl sulfone, benzyl 2-methylallyl sulfone, benzyl3-ethoxypropyl sulfone, p-methylbenzyl ethyl sulfone, pbromobenzyl allylsulfone, benzyl cyclohexyl sulfone and the like sulfones of thisinvention to produce tablets suitable for oral administration as ananti-inflammatory, anti-pyretic and/or analgesic according to the methodof this invention.

EXAMPLE 2 A mixture of 50 parts of benzyl ethyl sulfone, 3 parts of thecalcium salt of lignin sulphonic acid, and 237 parts of water isball-milled until the size of substantially all of the particles ofbenzyl ethyl sulfone is less than 10 microns. The suspension is dilutedwith a solution containing 3 parts of sodium carboxymethylcellulose and0.9 part of the butyl ester of p-hydroxybenzoic acid in 300 parts ofwater. There is thus obtained an aqueous suspension suitable for oraladministration for therapeutic purposes.

EXAMPLE 3 A mixture of 250 parts of benzyl butyl sulfone, 200 parts ofmaize starch and 30 parts of alginic acid is mixed with a sufficientquantity of a 10 percent aqueous paste of maize starch, and granulated.The granules are dried in a current of warm air-and the dry granules arethen passed through a l6-mesh screen, mixed with 6 parts of magnesiumsterate and compressed into tablet form to obtain tablets suitable fororal administration.

EXAMPLE 4 A mixture of 500 parts o-chlorobenzyl methyl sulfone, 60 partsof maize starch and 20 parts of gum acacia is granulated with asufficient quantity of water. The mass is passed through a l2-meshscreen and the granules are dried in a current of warmi air. The drygranules are passed through a l6-mesh screen, mixed with 5 parts ofmagnesium sterate and compressed into tablet form suitable for oraladministration.

EXAMPLE 5 A mixture of 25 parts of benzyl allyl sulfone, 30 parts ofsucrose, 0.5 part of acetyl alcohol polyethylene oxide condensate, 1part of polyvinyl pyrolidone, 0.25 part of methyl p-hydroxybenzoate andparts of water is ball-milled for several hours. After the incorporationof suitable coloring and flavoring agents, there is obtained an aqueoussuspension suitable for oral administration for therapeutic purposes.

EXAMPLE 6 5 parts of benzyl Z-methylcyclohexyl sulfone in a finelydivided form are mixed with 12 parts of powdered gum acacia, 0.8 part ofpowdered tragacanth and 0.4 part of elixir of saccharin, and the wholeis mixed with 50 parts of arachis oil. The oily suspension is then mixedwith 50 parts water and there is thus obtained an emulsion suitable fororal administration.

Further illustrative of the active sulfone ingredients of thisinvention, and utilizable in the formulations described in Examples 1through 6 are: benzyl pentyl sulfone, benzyl isopentyl sulfone, benzyl2-methyl cyclopentyl sulfone, benzyl 2-butenyl sulfone, benzyl 3-butenyl sulfone, benzyl l-methyl allyl sulfone, benzyl 2- methyl allylsulfone, benzyl l-methylpropenyl sulfone, benzyl 2-methylpropenylsulfone, benzyl vinyl sulfone, benzyl 2bromoethyl sulfone, benzyl2-chloroethyl sulfone, benzyl 2-chloropropyl sulfone, benzyl 3-chloropropyl sulfone, benzyl 2-chlorocyclohexyl sulfone, benzyl2,3-dichloropropyl sulfone, benzyl 2,3- dibromopropyl sulfone, benzyl2,3,3-trichloropropyl sulfone, benzyl 2-ethoxyethyl sulfone, benzyl 1,2-dichlorovinyl sulfone, benzyl 1,2,2-trichlorovinyl sulfone, benzyl3-bromoallyl sulfone, benzyl 3- bromopropenyl sulfone, benzyl3-chloropropenyl sulfone, benzyl 3,3-dichloroallyl sulfone,a-methylbenzyl methyl sulfone, m-chlorobenzyl methyl sulfone,pchlorobenzyl methyl sulfone, 3,4-dimethylbenzyl ethyl sulfone,3,4-dimethylbenzyl methyl sulfone, 3,4- dichlorobenzyl ethyl sulfone,o-methylbenzyl allyl sulfone, p-methylbenzyl allyl sulfone,m-methylbenzyl allyl sulfone, o-nitrobenzyl allyl sulfone, p-nitrobenzylallyl sulfone, m-nitrobenzyl allyl sulfone, pchlorobenzyl 2-chloroethylsulfone, p-chlorobenzyl 1,2-dichlorovinyl sulfone, a,a-dimethylbenzylisobutyl sulfone, a-ethylbenzyl methyl sulfone, a-allylbenzyl methylsulfone, a-phenylbenzyl methyl sulfone, aethoxycarbonylbenzyl methylsulfone, a,a-diphenylbenzyl methyl sulfone,2,4-difluoro-a,a-dimethylbenzyl methyl sulfone, 3-tertiarybutylbenzylmethyl sulfone,

2-hydroxymethylbenzyl methyl sulfone, 2- aminomethylbenzyl methylsulfone, 2- dimethylaminomethylbenzyl methyl sulfone, 3-trifluoromethylbenzyl methyl sulfone, 4-methoxybenzyl methyl sulfone,2-methoxybenzylmethyl sulfone, 3-methoxybenzyl methyl sulfone,4-phenylbenzyl methyl sulfone, 4-benzyloxybenzyl methyl sulfone, 2-benzyloxybenzyl methyl sulfone, 2-,3-, and 4- fluorobenzyl methylsulfone, 2-bromobenzyl methyl sulfone, 2-nitrobenzyl methyl sulfone, 2-,and 4- aminobenzyl methyl sulfone, Z-dimethylaminobenzyl methyl sulfone,2-carboxybenzyl methyl sulfone, 2- methoxycarbonylbenzyl methyl sulfone,2-carbamoylbenzyl methyl sulfone, 2 -N,N-dimethylcarbamoylbenzyl methylsulfone, 2-acetylbenzyl methyl sulfone, 2,4-dichlorobenzyl methylsulfone, 3,4-dichlorobenzyl methyl sulfone, 2,6-dichlorobenzyl methylsulfone and 3,5-dichlorobenzyl methyl sulfone.

The aralkyl hydrocarbyl sulfones of this invention are produced by wellknown techniques such as oxidation of the corresponding sulfide withdilute hydrogen peroxide, or permanganate and glacial acetic acid, andheating; alkylation of the corresponding sulfinate. These methods aremore fully set forth in Synthetic Organic Chemistry, John Wiley & Sons,Inc., New York, pages 801-803 (1953), and the following descriptions andexamples.

The methods are illustrated by the reaction schemes: I.

I X o som 11 02 I Y lt Y (Z): II.

Reaction H A is normally conducted by adding a carbon tetrachloridesolution of bromine to a carbon tetrachloride solution of theappropriate toluene under reflux and the influence of ultravioletirradiation. Other halogenated hydrocarbons such as chloroform,tetrachloroethylene and the like can be used equally well at anyreasonable temperature, reflux being most convenient.

Reaction III A is normally conducted by treating a benzene solution of abenzyl alcohol with thionyl chloride at reflux temperature for about 1hour. This can also be performed in other inert solvents such astoluene, chloroform, tetrachloride and the like or by using excessthionyl chloride as solvent. Any temperature from about 50 to 150 C. issatisfactory, but again reflux temperature is most convenient.

Reactions ll B and III B are identical and are normally conducted byrefluxing an alcoholic solution of equimolar amounts of the benzylhalide and sodium methyl sulfinate monohydrate for about 2 hours,followed by cooling which usually results in crystallization of theproduct. Alcohols such as methanol, ethanol, propanol and the like aresatisfactory solvents. Heating for 2 hours is usually sufficient, butextended reaction times can be conveniently used.

Reaction IV is usually performed by treating a benzyl sulfone withsodium hydride in dimethyl formamide, warming to 50-60 C. for a shorttime and then adding an iodohydrocarbon to the chilled mixture withstirring. The product is conveniently isolated by pouring onto ice andextracting it with ether. Other solvents utilizable in this reaction aretetramethyl urea, glycine, diglycine and the like.

EXAMPLE 7 2-N,N-Dimethylcarbamoylbenzyl Methyl Sulfone A.2-Carboxybenzyl methyl sulfone To a suspension of 7 g. ofZ-carboxybenzyl methyl sulfide in 50 ml. of glacial acetic acid there isadded portionwise with stirring 9 ml. of 30 percent hydrogen peroxidewhile controlling the temperature near 20 with an ice bath. The mixtureis then stirred at room temperature for 2 hours and on a steam bath for1 hour. The mixture is poured into 500 ml. water and is extracted 3times with ml. methylene chloride. After drying over anhydrous magnesiumsulfate, the extract is diluted to 1 liter with petroleum-ether to give3.4 g.

2-Carboxybenzyl methyl sulfone (1.0 g.) and 5ml. of A thionyl chlorideare refluxed with stirring for a hour. The excess thionyl chloride isevaporated under reduced pressure. The residue is dissolved inmethylenechloride and the solvent is evaporated to dryness. The residual2-chlorocarbonylbenzyl methyl sulfone is dried in vacuo over potassiumhydroxide.

The acid chloride is dissolved in 30 ml. of methylenechloride andgaseous anhydrous dimethylamine is added until the solution isdefinitely basic. The mixture is concentrated to dryness under reducedpressure. The residual oil is coevaporated twice with water in vacuo.Water is added and the product is extracted three times withmethylenechloride. The extract is dried over magnesium sulfate andconcentrated in vacuo to a colorless oil which crystallizes slowly. Theproduct was recrystallized from a mixture of ml. methylenechloride and70 ml. of petroleum ether to give 0.9 g., m.p. 1l7-1 18 C., of2-N,N-dimethylcarbamoylbenzyl methyl sulfone.

Analysis: Calculated for C H O NS: C, 54.78; H,

6.27; S, 13.29 percent. Found: C, 54.23; H, 5.83; S, 13.26 percentEXAMPLE 8 2-Benzy1oxybenzyl Methyl Sulfone A. 2-BenzyloxybenzylchlorideTo a solution of 40 g. of 2-benzyloxybenzyl alcohol in 400 ml. of drybenzene and 3 drops of dry pyridine is added 20.4 ml. of thionylchloride and the solution is refluxed with stirring for 1 hour. Thesolution is cooled, washed 12 times with 500 ml. of cold water and isdried over anhydrous magnesium sulfate. The solvent is evaporated invacuo to a colorless oil weighing 44.3 g. B. 2-Benzyloxybenzyl methylsulfone A solution of 11.63 g. of 2-benzyloxybenzylchloride and 6 g. ofsodium methylsulfinatemonohydrate in 100 ml. of absolute alcohol isrefluxed with stirring for 2 hours. The mixture is cooled, filtered andevaporated in vacuo to a crystalline residue. The crystals are collectedby filtration after slurrying in water, washed with water, air-dried andrecrystallized from 65 ml. of methanol to give 8.43 g., m.p. ll7-1 19C.

Analysis: Calculated for C ,,H O S: C, 65.19; H,

5.87; S, 11.60 percent Found: C, 65.70; H, 5,58; S, 11.96 percentEmploying the methods disclosed in Example 8, but substituting for2-benzyloxybenzyl alcohol an equimolar amount of the substituted benzylalcohols in Table I, there is obtained the tabulated products.

sulfone 2-methoxybenzyl alcohol Z-methoxybenzyl methyl sultone 94-96a-phenylbcnzyl alcohol a-phenylbenzyl methyl sulfone 1 33-5S-methoxybenzyl alcohol B-methoxybenzyl methyl sult'one 44-54-benzyloxybenzyl 4-benzyloxybenzyl alcohol methyl sulfone 174-5a-ethylbenzyl alcohol a-ethylbenzyl methyl sulfone 79.0-79.5

EXAMPLE 9 2,4-Difluorobenzyl Methyl Sulfone A. 2,4-DifluorobenzylbromideA solution of 25.3 g. of 2,4-difluorotoluene in 200 ml. of dry carbontetrachloride is heated, with stirring to reflux while adding 27 g. ofbromine in 50 ml. of carbon tetrachloride is added dropwise underultraviolet irradiation. After the bromine color disappears (about '15hour), the solution was cooled, washed with ice water, dried overmagnesium sulfate and concentrated to dryness in vacuo to yield 37.1 g.of 2,4- difluorobenzylbromide. 1 B. 2,4-Difluorobenzyl Methyl SulfonePrepared from 8.6 g. 2,4-difiuorobenzylbromide and 5.0 g. sodium methylsulfinate monohydrate as described in Example 8 B to give 2.8 g. 2,4-difluorobenzyl methyl sulfone, m.p. 94-95 C.

Analysis: Calculated for C H F O S: C, 46.60; H,

3.91 percent Found: C, 46.92; H, 3.82 percent Employing the methodsdisclosed in Example 9, but substituting for 2,4-difluorotoluene, anequimolar amount of the substituted benzyl alcohols in Table I1, thereis obtained the tabulated products.

TABLE 11 Starting Material Product m.p. (C.)

Z-t'luorotoluene 2-fluorobenzyl methyl sulfone -92 4-fluorotoluene4-fluorobenzyl methyl sulfone 107-1 10 3-fluorotoluene 3-fluorobenzylmethyl sulfone -103 2,4-dichlorotoluene 2,4dichlorobenzyl methyl sulfone1 12-15 3-trifluoromethyl- 3-trifluoromethylbenzyl toluene methylsulfone 11 1-12 3,4-dichlorotoluene 3,4-dichlorobenzyl methyl sulfone132-3 2,6-dichlorotoluene 2,6-dichlorobenzyl methyl sulfone 109-10Z-bmmotoluene 2-bromobenzyl methyl sulfone 85-7 3,5-dichlorotoluene3,5-dichlorobenzyl methyl sulfone 126-7 pentafluorotoluenepentafluorobenzyl methyl sulfone 129-30 2-fluoro-4-chloro-2-fluoro-4-chlorotoluene benzyl methyl sulfone 101-2 2,5-difluorotoluene2,5 -difluorobenzyl methyl sulfone 92-4 3-tertiarybutyl-3-tertiarybutylbenzyl toluene methyl sulfone 1 18-19 o-tolunitrileZ-cyanobenzyl methyl sulfone 133-34 EXAMPLE 10a,a-Dimethyl-2,4-Difluorobenzyl Methyl Sulfone 2,4-Difluorobenzyl methylsulfone (3.0 g.) is suspended in 30 ml. of dry dimethylformamide and 1.7g. (0.034 mole) of sodium hydride emulsion is added with stirring. Themixture is warmed at 50-60 C. for

20 minutes when gas evolution ceases. Methyl iodide (5.0 ml.) in 5.0 m1.dimethylforrnamide is added to the chilled mixture dropwise withswirling and the mixture is stirred in ice for hours, and overnight atroom temperature. The mixture is poured into cold water, and extractedwith ether. The extract is washed with water, dried over sodium sulfate,and concentrated to a yellow oil (2.5 g.). The oil is chromatographed on180 g. of silica gel, eluting as follows: 7 X 250 ml. portions ofpetroleum ether, 2 X 250 ml. portions of 5 percent benzene-petroleumether, 4 X 250 ml. portions of percent benzene-petroleum ether, 2 X 250ml. portions of 50 percent benzene-petroleum ether, 5 X 250 ml. portionsof benzene, 2 X 250 ml. portions of 10 percent ethyl acetate and 2 X 250ml. portions of 20 percent ethyl acetate-benzene. The last two fractionscontaining 2.0 g. of a mixture is distilled in vacuo at a bathtemperature of 115l50 C. to give 0.7 g. of oilya,adimethyl-2,4-difluorobenzyl methyl sulfone.

Analysis: Calculated for C H F O S: C, 51.24; H,

5.16; S, 13.69 percent Found: C, 50.54; H, 5.01; S, 13.64 percentEXAMPLE 11 a-Ethoxycarbonylbenzyl Methyl Sulfone A. Ethyla-Bromophenylacetate A solution of 9.45 g. of a-bromophenylacetic acidin 200 ml. of absolute alcohol is saturated with hydrogen chloride andstored at 20-25 for 3 days. The solution is evaporated to a small volumeand then distributed between ether and ice water. Excess sodiumbicarbonate is added, the ether layer is separated, dried over anhydroussodium sulphate and evaporated in vacuo to give 8.97 g. of oily ethyla-bromophenylacetate. B. a-Ethoxycarbonylbenzyl Methyl Sulfone A mixtureof 8.97 g. of ethyl a-bromophenylacetate, 8.9 g. of sodium methylsulfinate and 50 ml. of absolute alcohol is refluxed 16 hours. Thesolvent is evaporated in vacuo and the residue is distributed betweenchloroform and water. The chloroform layer is separated and the solventis evaporated in vacuo to leave the product.

Analysis: Calculated for C H O S: C, 54.54; H,

5.83; S, 13.23 percent Found: C, 54.50; H, 5.87; 13.49 percent EXAMPLE12 2-Nitrobenzyl Methyl Sulfone A solution of 10.8 g. (0.05 mole) of2-nitrobenzyl bromide and 6.0 g. (0.05 mole) of sodium methyl sult'matemonohydrate in 100 ml. of absolute alcohol is refluxed 2 hours. Thesolution is cooled, evaporated in vacuo and the residue is slurried inwater. The crystals are collected and recrystallized from 125 ml.absolute alcohol to give 6.47 g., m.p. l-116.

Analysis: Calculated for C H NO S: C, 44.64; H,

4.22; S, 14.90 percent Found: C, 44.50; H, 4.20; S, 15.52 percentEXAMPLE 13 5 methyl sulfone and 1.6 ml. of 37 percent formaldehyde in 50ml. methanol is hydrogenated over 0.5 g. of 5 percent palladium oncharcoal under 42 lbs. of hydrogen pressure until 5 equivalents ofhydrogen are absorbed. The catalyst is filtered off and the filtrate isevaporated in vacuo. The oily residue is dissolved in absolute alcohol,treated with hydrogen chloride gas and then evaporated to drynesswhereupon it crystallizes. The material is recrystallized twice fromalcohol to give 0.87 g., m.p. 175 190 C.

Analysis: Calculated for C H NO S. HCl: C, 48.08;

H, 6.46; S, 12.84 percent Found: C, 47.86; H, 6.26; S, 12.59 percentEXAMPLE 14 4-Aminobenzyl Methyl Sulfone A solution of 3.0 g. of4-nitrobenzyl methyl sulfone in methanol-acetic acid is hydrogenatedover Raney nickel. The catalyst is filtered off and the filtrate isconcentrated to dryness. The solid residue is crystallized from ml.methanol to give 1.07 g., m.p. l69-171 C Analysis: Calculated for C H NOS: C, 51.88; H,

5.99 percent Found: C, 52.09; H, 5.85 percent EXAMPLE l5a,a-Dimethylbenzyl Methyl Sulfone Employing the method of Example 10with 5.5 g. of a-methylbenzyl methyl sulfone, 50 ml. dimethyl formamideand 1.44 g. of a 50 percent sodium hydride emulsion, there is obtained1.5 g. of a,a-dimethylbenzy1 methyl sulfone, m.p. 8385 C.

Analysis: Calculated for C H O S: C, 60-59; H,

7.12 percent Found: C, 60.27; H, 6.90 percent EXAMPLE l6 a-AllylbenzylMethyl Sulfone A solution of 9.5 g. (50 mm) of benzyl methyl sulfone and3.83 g. (50 mm) of allyl chloride in dimethyl forrnamide is added withstirring to a suspension of 3.4 g. (70 mm) of a 53 percent sodiumhydride emulsion in 150 ml. dimethyl formamide. The mixture is heated 1hour at 100 C., cooled to 23 C., and treated with 5 g. (0.1 mole) ofammonium chloride. The mixture is diluted with 2liters of water andextracted with methylene chloride to give 11.2 g. of oil. The oil ischromatographed on silica gel column 3.2 cm. X cm. with a methylenechloride-methanol (99:1) mixture, 1 liter fractions being collected.Fractions 5 and 6 are combined and concentrated to give 7.3 g. of oilwhich crystallizes. The product is recrystallized from ether-petroleumether to give 3.2 g. of a-allylbenzyl methyl sulfone, m.p. 4849 C.

Analysis: Calculated for C H O S: C, 62.84; H,

6.71; S, 15.22 percent Found: C, 62.72; H, 6.49; S, 15.33 percent l3EXAMPLE 17 2-Methoxycarbonylbenzyl Methyl Sulfone A solution of 1 g. of2-chlorocarbonylbenzyl methyl sulfone (see Example 7, Steps A and B) in50 ml. of methanol is refluxed 1.5 hours, and concentrated to dryness invacuo. The residue is dissolved in methylene chloride, washed withdilute sodium bicarbonate solution and water, dried over anhydrousmagnesium sulfate and concentrated to dryness to give 0.55 g. crystalswhich after two recrystallizations from methylene chloride-petroleumether solution has m.p. 8990 C.

Analysis: Calculated for C H O S: C, 52.62; H,

5.30; S, 14.05 percent Found: C, 52.26; H, 5.19; S, 14.29 percentEXAMPLE 18 2-Carbamoylbenzyl Methyl Sulfone Gaseous ammonia is added toa solution of 1 g. 2- chlorocarbonylbenzyl methyl sulfone (see Example7) in 30 ml. of methylene chloride. The colorless crystals that separateare collected and washed with water. The solids are recrystallized twicefrom methanol to give 0.54 g., m.p. 215-216 C.

Analysis: Calculated for C H O NS: C, 50.69; H,

5.20; S, 15.03 percent Found: C, 50.74; H, 5.23; S, 14.70 percentEXAMPLE 19 Z-Aminomethylbenzyl Methyl Sulfone Hydrochloride A mixture of1 g. (0.005 mole) of 2-cyanobenzyl methyl sulfone (see Example 9), ml.of ethanol, 5 ml. of liquid ammonia and 7% teaspoon of Raney nickel istreated for 3 hours at 75, under 1,500 p.s.i. of hydrogen pressure. Themixture is diluted with 200 ml. of ethanol, filtered, and concentratedin vacuo to 1.3 g. solid. The solid is treated with dilute hydrochloricacid and concentrated to dryness to give 1.4 g. solid. Thishydrochloride is dissolved in water treated with alkali, and the freebase is extracted out with methylene chloride. The dried solution istreated with dry hydrogen chloride and concentrated to dryness to give0.54 g. of residue which is recrystallized from absolute alcohol to give0.37 g., m.p. 205-207 C.

Analysis: Calculated for C H NO S. HCl: C, 45.86;

H, 5.94; S, 13.56 percent Found: C, 45.99; H, 5.74; S, 13.51 percentEXAMPLE 20 Z-Dimethylaminomethylbenzyl Methyl Sulfone Employing themethod of Example 13 but utilizing 1.46 g. (0.0062 mole) of2-aminomethylbenzyl methyl sulfone hydrochloride, 10 ml. of water and200 ml. of 37 percent formaldehyde, there is prepared 1.15 g. ofZ-dimethylaminomethylbenzyl methyl sulfone, m.p. 232-234 C.

Analysis: Calculated for C H NO S. HCl: C, 50.08;

H, 6.88; S, 12.15 percent Found: C, 50-45; H, 6.90; S, 13.94 percentEXAMPLE 21 2-Arninobenzyl Methyl Sulfone Hydrochloride A mixture of 2.0g. (0.0092 mole) of Z-nitrobenzyl methyl sulfone (Example 12), ml. ofmethanol and 0.4 g. of 5 percent palladium on charcoal catalyst isshaken under 40 lbs. of hydrogen pressure until three equivalents ofhydrogen are absorbed. The mixture is filtered and the filtrate isconcentrated in vacuo to 1.7 g. of solid. One gram of the solid isdissolved in absolute alcohol, treated with dry hydrogen chloride andconcentrated in vacuo to 1.3 g. of a crystalline residue which aftercrystallizing from ethanol has m.p. 1851 9 5 C.

Analysis: Calculated for C l-1 N0 8. HCl: C, 43.34;

H, 5.47; S, 14.46 percent Found: C,43.18; H, 5.24; S, 13.81 percentEXAMPLE 22 Z-Hydroxymethylbenzyl Methyl Sulfone A solution of 1.77 g.(0.007 mole) of 2-methoxycarbonylbenzyl methyl sulfone in ml. ether and50 m1. tetrahydrofuran is added dropwise to a stirred mixture of 0.5 g.lithium aluminum hydride in ether. After stirring 45 minutes there isadded 3 ml. of ethyl acetate in 15 ml. of ether, then 3 ml. of methanolin 15 ml. of ether and finally 15 ml. of a saturated solution of sodiumsulfate. The mixture is filtered, dried over magnesium sulfate andconcentrated in vacuo to 1.8 g. of oil. The oil is purified bychromatography on 40 g. silica gel with methylene chloride as solvent.The product is collected and recrystallized from methylenechloridepetroleum ether to give 0.47 g., m.p. 75-77 C.

Analysis: Calculated for C H O S: C, 53.98; H, 6.04;

S, 16.01 percent Found: C, 53.73; H, 5.96; S, 16.71 percent EXAMPLE 232-Acetylbenzyl Methyl Sulfone A Grignard reagent prepared from 0.8 g.(0.034 mole) of magnesium and 4.8 g. (0.034 mole) of methyl iodide inether is treated with 3.5 g. (0.019 mole) of cadmium chloride andrefluxed 1 hour. The solution is cooled and 3.64 g. of2-chlorocarbonylbenzyl methyl sulfone in 40 ml. benzene is addeddropwise and the mixture is stirred and refluxed 2 hours. The mixture ispoured onto ice in 40 m1. of 2.5N hydrochloric acid. The organic phaseis separated by extraction with benzene-ether, dried and concentrated invacuo to 3.3 g. oil. After purifying by chromatography on silica gelwith methylene chloride and finally crystallizing from ether-petroleumether there is obtained 0.13 g., m.p. 68-70 C.

Analysis: Calculated for C H O S: C, 56.58; H,

5.70; S, 15.10 percent Found: C, 56.56; H, 5.91; S, 15.31 percent Whatisclaimed is: l. A compound of the structural formula where R and R" aremembers selected from the group consisting of hydrogen, lower alkyl,lower alkenyl or phenyl, with the proviso that if R and R" are the same,they are selected from the group consisting of hydrogen, lower alkyl andphenyl, and if they are different one of them is hydrogen;

Z is hydrogen or fluorine; X and Y are members selected from the groupconsisting of hydrogen, hydroxyloweralkyl,

haloloweralkyl, loweralkoxy, phenyl, benzyloxy and fluoro, with theproviso that if Z is fluorine, X and Y are hydrogen or fluorine and if Zis hydrogen and X and Y are both other than hydrogen, they are fluorine;with the further proviso that X, Y and Z may not be all hydrogen. 2. Acompound according to claim 1 where R and R" are hydrogen and X, Y, andZ are hydrogen or fluoro provided that X, Y, and Z are not all hydrogen.

3. 2,4-Difluorobenzyl methyl sulfone according to claim 2.

4. A process for the preparation of a compound of the formula where Rand R" are members selected from the group consisting of hydrogen, loweralkyl or lower alkenyl with the proviso that if R and R" are the same,they are lower alkyl and if they are different, one of them is hydrogen;

wherein X is a member selected from the group consisting of Cl, Br and Fattached to the 6-position or Cl attached to the 4-position, and n is 2.

6. A compound as claimed in claim 5, namely, 2,6- dichlorobenzylmethylsulfone.

7. A compound as claimed in claim 5, namely, 2,4- dichlorobenzylmethylsulfone.

2. A compound according to claim 1 where R'' and R'''' are hydrogen andX, Y, and Z are hydrogen or fluoro provided that X, Y, and Z are not allhydrogen.
 3. 2,4-Difluorobenzyl methyl sulfone according to claim
 2. 4.A process for the preparation of a compound of the formula where R'' andR'''' are members selected from the group consisting of hydrogen, loweralkyl or lower alkenyl with the proviso that if R'' and R'''' are thesame, they are lower alkyl and if they are different, one of them ishydrogen; Z is hydrogen or fluorine; and X and Y are members selectedfrom the group consisting of hydrogen, hydroxyloweralkyl,haloloweralkyl, loweralkoxy, phenyl, benzyloxy and fluoro, with theproviso that if Z is fluoride, X and Y are hydrogen or fluorine and if Zis hydrogen and X and Y are both other than hydrogen, they are fluorine;which comprises reacting a benzyl methyl sulfone with sodium hydride,followed by treatment with a lower alkyl or loweR alkenyl iodide.
 5. Acompound of the formula wherein X is a member selected from the groupconsisting of Cl, Br and F attached to the 6-position or Cl attached tothe 4-position, and n is
 2. 6. A compound as claimed in claim 5, namely,2,6-dichlorobenzylmethyl sulfone.
 7. A compound as claimed in claim 5,namely, 2,4-dichlorobenzylmethyl sulfone.